Identification of Umbre Orthobunyavirus as a Novel Zoonotic Virus Responsible for Lethal Encephalitis in 2 French Patients With Hypogammaglobulinemia

International audienceBackground: Human encephalitis represents a medical challenge from a diagnostic and therapeutic point of view. We investigated the cause of 2 fatal cases of encephalitis of unknown origin in immunocompromised patients.Methods: Untargeted metatranscriptomics was applied on the brain tissue of 2 patients to search for pathogens (viruses, bacteria, fungi, or protozoans) without a prior hypothesis.Results: Umbre arbovirus, an orthobunyavirus never previously identified in humans, was found in 2 patients. In situ hybridization and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) showed that Umbre virus infected neurons and replicated at high titers. The virus was not detected in cerebrospinal fluid by RT-qPCR. Viral sequences related to Koongol virus, another orthobunyavirus close to Umbre virus, were found in Culex pipiens mosquitoes captured in the south of France where the patients had spent some time before the onset of symptoms, demonstrating the presence of the same clade of arboviruses in Europe and their potential public health impact. A serological survey conducted in the same area did not identify individuals positive for Umbre virus. The absence of seropositivity in the population may not reflect the actual risk of disease transmission in immunocompromised individuals.Conclusions: Umbre arbovirus can cause encephalitis in immunocompromised humans and is present in Europe

Identification d’un nouvel arbovirus neurotrope en France : le virus Umbre

International audienceNotre laboratoire a mis en place une collaboration avec le laboratoire de neuropathologie de l’hôpital de la Pitié-Salpêtrière pour explorer une série post-mortem de cas d’encéphalites humaines d’étiologie inconnue par un séquençage NGS profond et non ciblé du transcriptome, à la recherche de séquences de pathogènes. Le virus Umbre, un virus du genre orthobunyavirus, a été identifié chez deux patients immunodéprimés décédés en 2013 et 2019. Le virus infecte des neurones du cortex cérébral, la moelle épinière et le foie. Le virus Umbre a été décrit initialement dans les années 1950 dans des populations de moustiques Culex en zone Asie Pacifique, mais n’avait auparavant ni été isolé chez des mammifères (dont l’homme), ni détecté en Europe. Cette infection par le virus Umbre chez deux patients français, dont l’un vivait dans la région Occitanie et n’avait jamais voyagé en dehors de France métropolitaine, et l’autre avait fait une croisière en méditerranée avant l’apparition des symptômes, nous a amené à rechercher l’origine de la contamination dans des moustiques. Une investigation réalisée en partenariat avec le CIRAD de Montpellier et l’EID Méditerranée a permis d’identifier des séquences du genre orthobunyavirus très proches du virus Umbre dans des moustiques Culex de Camargue. Une enquête sérologique par un test développé à l’Institut Pasteur sur une population du sud de la France composée d’environ 300 personnes « contrôles » et d’une vingtaine de cas « encéphalites » n’a pas mis en évidence de réponse anticorps contre le virus Umbre. Ce résultat suggère que la fréquence de l’infection dans la population générale est au plus faible, ce qui ne reflète donc pas le risque pour les personnes immunodéprimées. Cette découverte d’un nouvel arbovirus responsable d’encéphalite, et son existence en France, présente un intérêt particulier en matière de santé publique

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy

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Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

International audienceInherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases

Treating asymptomatic bacteriuria before immunosuppressive therapy during multiple sclerosis: Should we do it?

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Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study

Online ahead of printInternational audienceIntroduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS.Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion.Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9).Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Multiple sclerosis (MS) disease risk is associated with reduced sunexposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (n(NationMS) = 946, n(BIONAT) = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-beta-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests benefidal effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS